The sequencing of the human genome and identification of candidate genes will allow substantial innovation in the study of the contribution of genetics to diseases of old age, especially in conjunction with emerging technologies to understand the corresponding proteomics. Understanding genetic and environmental contributions and their interactions could create novel opportunities to prevent disease and limit disability. The Age, Gene/Environment Susceptibility (AGES) Study was initiated to examine genetic susceptibility and gene/environment interaction as these contribute to phenotypes common in old age. The study has four major focus areas: neurocognitive conditions (cognition, dementia, depression, neurosensory vision and hearing), cardiovascular health (atherosclerosis, arterial distensibility, ventricular and valvular disease), musculoskeletal conditions (spine and hip osteoporosis, hip osteoarthritis, strength and function), and body composition and metabolic disease (obesity, sarcopenia, hyperglycemia/diabetes).Baseline enrollment of 5674 men and women is completed and a follow-up exam is underway. The study is conceived of as a 3-part study. The major aspect of the study is a cross-sectional examination of Reykjavik Study participants to define phenotypes for candidate gene studies. However, these phenotypes will also be used as end-points to be examined in relation to the earlier risk factors collected as part of the Reykjavik Study. This will allow enhanced understanding of factors contributing to disease in old age, apart from genetic factors. Lastly, these phenotypes can be examined in relation to selected outcomes cause-specific mortality, coronary heart disease, fractures, and cancers. With the exception of the apolipoprotein E gene, the importance of genetic contributions to chronic conditions of old age is unclear. Single gene mutations have been associated with early-onset forms of these chronic conditions. Later life disease is hypothesized to reflect multiple genes with small contributions and it has proven difficult to identify these genes using conventional methods that were useful for identification of the early-onset single gene mutations. The AGES Study has been designed to address many of the limitations of genetic epidemiology studies of late-life disease. These include sufficient power, the relatively genetically homogeneous Icelandic population along with the available information about familial relationships from genealogies. Most important is the emphasis on quantitative traits rather than either self-reported conditions or medical diagnosis. The focus areas for the AGES Study also share etiologic hypotheses regarding risk factors, therefore allowing complementary genetic studies of polymorphisms as these might pertain to multiple health conditions. For instance, atherosclerosis, osteoporosis, obesity and glucose abnormalities, Alzheimers Disease and vascular dementia, share hypotheses related to inflammation. We have identified this as one of the areas for genetic investigation in the AGES Study and pla to examine whether polymorphisms in the genes for proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-6, interleukin-1, or genetic variation in the anti-inflammatory cytokines, interleukin-4, will be associated with phenotypes of these diseases. Another such area involves cells derived from mesechymal stem cells including osteocytes, chondrocytes, myocytes, adipocytes and stroma. As subjects age and change physical activity, there appears to be deposition of fat within muscle and within bone, linked to sarcopenia and to osteoporosis. These processes may be regulated by PPAR-c;genotyping for one condition will allow efficient investigations of potentially related conditions. Several specific research hypotheses include: Alzheimers disease is associated with vascular damage that resultsfrom mid-life risk factors such as blood pressure, cholesterol, fasting and post-challenge glucose, and insulin. These risk factors will also be associated with MRI-determined vascular changes, aside from stroke, and will be mediated by markers of inflammation. Genetic susceptibility to vascular changes will contribute to the associations between cardiovascular risk factors and AD. Subclinical late-life atherosclerosis (measured by carotid thickening, aortic and coronary calcification, and low ankle-arm blood pressure ratio, indicative of peripheral arterial disease) reflects the effect of risk factors from midlife such as blood pressure, smoking, cholesterol, fasting and post-challenge glucose, and sedimentation rate. These will interact with candidate genes such as apolipoprotein e4. Lifelong participation in physical activity (measured from earlier and current questionnaires) will be associated with preservation of muscle mass in old age, less fatty infiltration of muscle, lower visceral fat, and higher bone mineral density in both the spine and hip. This will interact with polymorphisms in candidate genes such as the ACE polymorphism that are hypothesized to affect muscle development. There will be a strong relationship between clinically recognized and subclinical CVD and low bone mineral density in the spine and the hip. This relationship will be modified by genetic factors related to inflammation, particularly polymorphisms of the IL-6 and TNF-alpha genes. Although located in Iceland, Icelanders and many U.S. citizens share a common genetic heritage from Northern Europe. It is hoped that the results of this study, besides contributing to knowledge of genetic factors influencing diseases of old age, may also be generalize to the U.S. population.